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WO2017013023A1 - Vecteur de virus orf recombiné - Google Patents

Vecteur de virus orf recombiné Download PDF

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Publication number
WO2017013023A1
WO2017013023A1 PCT/EP2016/066926 EP2016066926W WO2017013023A1 WO 2017013023 A1 WO2017013023 A1 WO 2017013023A1 EP 2016066926 W EP2016066926 W EP 2016066926W WO 2017013023 A1 WO2017013023 A1 WO 2017013023A1
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WIPO (PCT)
Prior art keywords
orfv
recombinant
promoter
antigen
foreign gene
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PCT/EP2016/066926
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German (de)
English (en)
Inventor
Hans-Joachim Rziha
Ralf Amann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eberhard Karls Universitaet Tuebingen
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Eberhard Karls Universitaet Tuebingen
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Priority to AU2016294855A priority Critical patent/AU2016294855B2/en
Priority to DK16741595.9T priority patent/DK3325631T3/da
Priority to KR1020187004903A priority patent/KR102259277B1/ko
Priority to CA2993263A priority patent/CA2993263A1/fr
Priority to CN201680053548.XA priority patent/CN108026542B/zh
Priority to BR112018001121-5A priority patent/BR112018001121B1/pt
Priority to EA201890351A priority patent/EA201890351A1/ru
Priority to KR1020217015985A priority patent/KR102433709B1/ko
Priority to EP16741595.9A priority patent/EP3325631B1/fr
Priority to NZ73928616A priority patent/NZ739286A/en
Priority to EP25156960.4A priority patent/EP4545094A3/fr
Priority to IL257025A priority patent/IL257025B2/en
Application filed by Eberhard Karls Universitaet Tuebingen filed Critical Eberhard Karls Universitaet Tuebingen
Priority to MX2018000845A priority patent/MX2018000845A/es
Priority to JP2018522854A priority patent/JP7092663B2/ja
Priority to CN202211462316.3A priority patent/CN116445547A/zh
Publication of WO2017013023A1 publication Critical patent/WO2017013023A1/fr
Priority to US15/875,389 priority patent/US11286500B2/en
Priority to PH12018500155A priority patent/PH12018500155A1/en
Anticipated expiration legal-status Critical
Priority to ZA2018/01091A priority patent/ZA201801091B/en
Priority to AU2020264302A priority patent/AU2020264302B2/en
Priority to US17/655,316 priority patent/US20220204992A1/en
Ceased legal-status Critical Current

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    • C12N2710/24011—Poxviridae
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    • C12N2710/24241—Use of virus, viral particle or viral elements as a vector
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a recombinant Orf virus vector, a cell containing the recombinant Orf virus vector, a composition of the invention containing the recombinant Orf virus vector and / or the cell according to the invention, the use of the inventive recombinant Orf virus vector for expression of a foreign gene and a nucleic acid molecule coding for an Orf virus vector promoter.
  • Viral vectors are used in biotechnology to generate genetic material in
  • Viral vectors therefore represent a significant platform technology, in particular for the production of recombinant vaccines, which, in addition to the classical prevention of infectious diseases, are increasingly being used to develop new, innovative therapy concepts, such as, for example, therapeutic tumor immunization.
  • the orf virus belongs to the family of poxviruses and has a
  • ORFV are enveloped, complex dsDNA viruses of wool-ball-like morphology and have an average size of about 260 x 160 nm. They have a linear, GC-rich, approximately 130 to 150 kbp DNA genome whose central area is located on both sides of ITR.
  • early viral gene expression in which viral mRNA is synthesized under the control of pox virus-specific early promoters, and when the core structure is dissolved, the viral DNA is released in the cytoplasm, in contrast to the transcription of early genes , which is exclusively under the control of viral TF, subsequent "intermediate” and “late” gene transcription rely on the assistance of cellular TF.
  • poxviral expression of early genes unlike expression of intermediate and latent genes, requires neither replication of viral DNA nor virus production.
  • the ORFV is characterized by a very narrow natural host range, which includes sheep and goat. Infections are via lesions of the skin that allow the virus to enter. The proliferation of the dermatropic virus is then limited to regenerative keratinocytes, causing a contagious dermatitis or ecthyma contagiosum. This usually mild, self-limiting infection manifests as a localized cutaneous or mucosal lesion, with the pustular formation induced by the massive infiltration of polymorphonuclear lymphocytes occurring mainly on the mouth and udder. The lesion heals after 4 to 6 weeks without scarring.
  • ORFV is considered a zoonotic pathogen and in rare cases on the injured skin can be transmitted to humans. After infection, localized, mod- ular swelling, usually confined to the fingers and hands, and occasionally swelling of the lymph nodes and fever. Usually the course is harmless, free from complications and completely heals within three to eight weeks without clinical after-effects. In immunosuppressed individuals, serious infection, which, however, completely healed after treatment with antivirals such as cidofovir or imiquimod.
  • ORFV is of interest for the production of recombinant vaccines. Compared to
  • Orthopoxviruses are ORFV characterized by a very narrow natural host tropism, which includes sheep and goat.
  • an inhibitory "pre-immunity" to the vector caused by a natural infection as observed in the most common viral vectors of the vaccinia and adenoviruses, can be virtually excluded in man.
  • the exceptionally weak and short-lived ORFV-specific vector immunity enables very effective booster and / or booster immunizations with ORFV-based vaccines directed against other pathogens.
  • ORFV The administration of ORFV leads in permissive, but also non-permissive hosts to a strong immunostimulatory reaction, which is characterized by a pronounced induction of innate immune mechanisms and the release of interferons, cytokines and chemokines.
  • dendritic cells Shortly after immunization, dendritic cells accumulate at the site of injection and then initiate a specific adaptive immune response by activating T and B cells.
  • vaccines derived from inactivated viruses or live vectors which usually induce a humoral-resistant immune response
  • the balanced induction of the cellular and humoral immune responses after immunization with recombinant ORFV is a decisive advantage.
  • D1701 corresponding to the identical ORFV strain.
  • This vaccine which was known in inactivated form under the trade name Baypamun (Bayer) or Zylexis (Pfizer), was originally obtained by isolation of a wild-type virus from sheep and subsequent adaptation as a result of multiple passaging in bovine kidney culture cells. NEN. This was followed by further adaptation in African green monkey kidney cells (Vero cells), resulting in the preservation of the ORFV vector D1701-V. D1701-V is further attenuated and causes only asymptotic infections even in immunosuppressed sheep.
  • ORFV vectors select as insertion site the VEGF locus. This offers, according to current knowledge, the supposed advantage that the elimination of the vegf-e gene, which is under the control of a poxvirus-specific "early" promoter and is valid as a virulence factor, further attenuates the vector.
  • ORFV-based recombinant vaccines have been produced and tested in animal models.
  • recombinant ORFV vaccines are being used against various infectious diseases such as Aujeszky's disease, rabies, Borna's disease, influenza or classical swine fever.
  • ORFV Orf virus
  • nucleotide sequence is inserted into at least one of the insertion locus (IL) 1, 2 and 3, which are located in the ORFV genome in the following regions:
  • ORFV Orf virus
  • Parapoxvirus ovis falling viruses and virus strains understood, in particular the strain D1701.
  • a recombinant ORFV vector is understood to be an ORFV genome-based vector which is designed for the transport and / or expression of a foreign gene in biological (n) cells.
  • a foreign gene is not the ORFV genome
  • a promoter is understood as meaning such a nucleic acid segment which makes possible the regulated expression of the foreign gene in the ORFV vector according to the invention.
  • it is an ORF promoter, i. a promoter present in the wild-type ORFV genome or an optionally derived and optionally artificial promoter, such as a poxvirus promoter, CMV promoter, etc.
  • the position of the insertion locus IL 1, 2 and 3 according to the invention in the ORFV genome can be determined in various ways: by means of restriction fragments, the ORFV genes or open reading frame (OLR) or nucleotide positions in the ORFV genome ,
  • the traditional description of the localization of IL 1, 2, and 3 is based on restriction maps and the specification of restriction fragments on which the insertion regions lie.
  • the restriction map of ORFV is illustrative of strain D1701 in Cottone et al. (1998), Analysis of genomic rearrangement and subsequent gene deletion of the attenuated Orf virus strain D1701, Virus Research, Vol. 56, pages 53-67. The content of this publication is part of the present disclosure.
  • Hind /// fragment C, Kpn / fragment G, Bam / - fragment C / G, EcoR / fragment B means that this insertion locus is independent of the Hind // / Fragment C extends to the EcoR / fragment B.
  • IL 2 extends from Hind III fragment I-J to Eco R fragment A / E.
  • IL 3 extends from HindIII fragment G / D to EcoR fragment D.
  • the indication 006, 007 (dUTPase), 008 (G1 L-Ank), 009 (G2L) for IL 1 means that the insertion locus extends from the gene or OLR 006 up to the gene or OLR 009.
  • the indications in the parentheses refer to the coding products or encoded enzymatic activities, as far as they are currently known.
  • IL 1 is in a range which starts at nucleotide 400 to 600 (500 ⁇ 100) and ends at nucleotide 1800 to 3000 (2400 ⁇ 600).
  • IL 1 nt 496 - nt 2,750; nt 496 - nt 1 .912 and nt 51 1 - 2.750
  • IL 3 nt 15.656 - 17.849.
  • Insertion locus foreign genes can be stably integrated into the ORFV genome. This was surprising. Previously it was assumed that the regions affected by the insertion locus in the genome are required for virus replication or are unsuitable for the expression of foreign genes.
  • gene selection can be controlled by choosing the insertion locus. For example, the expression of foreign genes in IL 2 is reduced by a factor of 2 compared to the previously used VEGF locus. Furthermore, the choice of the promoter can specifically influence the strength and the time of expression of the foreign gene.
  • ORFV is one of strain D1701.
  • the promoter is an ORFV promoter, more preferably an early ORFV promoter, which more preferably has a nucleotide sequence selected from: SEQ ID NO: 1 (P1), SEQ ID NO: 1 2 (P2), SEQ ID NO: 3 (VEGF), SEQ ID NO: 4 (optimized early), SEQ ID NO: 5 (7.5 kDa promoter) and SEQ ID NO: 6 (consensus "early").
  • Promoters P1 and P2 are those newly developed by the inventors. The remaining promoters are derived from vaccinia virus and are described in other contexts in Davidson and Moss (1989), Structure of vaccinia virus late promoters, J. Mol. Biol., Vol. 210, pp. 771-784, and Yang et al. (201), Genome-wide analysis of the 5 'and 3' ends of vaccinia virus early mRNAs delineates regulatory sequences of annotated and aberrant transcripts, J. Virology, Vol. 85, No. 12, p.
  • P2 causes a significantly higher expression level than P1. This was surprising because the promoter P1 corresponds to 100% of the vaccine consensus sequence, but not P2.
  • the low expression of the "optimal" vaccinia virus promoter (Orthopox) in ORFV (Parapox) is a contradiction and surprising.
  • the promoter is arranged at a position of nt 28 ⁇ 10 to nt - 13 ⁇ 10 upstream with respect to the coding for the foreign gene nucleotide sequence.
  • This measure has the advantage that the promoter is located at such a position that allows a high level of expression and controlled expression of the foreign gene.
  • ORFV vector is used in at least one of IL 1, 2 or 3 more than one, preferably 2, 3, 4 or more, coding for a foreign gene and expressing this nucleotide sequence.
  • ORFV vector several foreign genes can be expressed. This embodiment is particularly suitable for the production of polyvalent vaccines which are simultaneously directed against several antigenic structures. In this case, several foreign genes, preferably 2, 3, 4 or more, can be expressed in each insertion locus.
  • the recombinant ORFV vector has a further coding for a foreign gene and this expressing nucleotide sequence, which is under the control of a preferably early ORFV promoter, and which is inserted an insertion locus in the ORFV genome localized in the vegf E gene.
  • This measure has the advantage that an insertion locus already described and well characterized in the prior art is used.
  • the use of the vegf locus can be used for targeted control of gene expression.
  • the expression of the foreign gene can be compared to one of the new expression loci, e.g. IL 2, be increased.
  • ORFV vector selected from the groups of the following antigens: - viral antigen, preferably
  • Rabies virus antigen including glycoprotein (RabG);
  • Influenza A antigen including nucleoprotein (NP), hemagglutinin (HA), neuraminidase (NA);
  • Tumor antigen preferably viral tumor antigen, including HPV-selective viral tumor antigen
  • tumor-associated antigen including viral tumor-associated antigen, including HPV-selective viral tumor-associated antigen
  • - parasitic antigen preferably plasmodium antigen
  • This measure has the advantage that particularly significant antigens, in particular for the production of vaccines, can be expressed via the recombinant ORFV virus according to the invention.
  • Another object of the present invention relates to a biological cell
  • a mammalian cell preferably a Vero cell containing the ORFV vector of the invention.
  • Another object of the present invention relates to a composition, preferably a pharmaceutical composition containing the ORFV vector according to the invention or / and the cell according to the invention.
  • the pharmaceutical composition may preferably be a vaccine, more preferably a polyvalent vaccine.
  • Recombinant ORFV vectors apply correspondingly to the cell according to the invention and the composition according to the invention.
  • Another object of the present invention relates to the use of the recombinant ORFV vector according to the invention for the expression of at least one foreign gene, more preferably for the expression of at least one foreign gene-containing vaccine (monovalent vaccine), more preferably from a at least two foreign gene-containing vaccine (polyvalent vaccine ).
  • a further subject matter of the present invention relates to a nucleic acid molecule coding for an ORFV promoter, preferably an early ORFV promoter, having a nucleotide sequence selected from the nucleotide sequences SEQ ID No. 1 (P1) and SEQ ID No. 2 (P2).
  • the nucleic acid molecule according to the invention codes for new ORFV promoters which are particularly suitable for the expression of foreign genes in the recombinant ORFV vector according to the invention.
  • the promoters cause a very strong, early gene expression.
  • Figure 1 shows the map of the HindIII restriction fragments of the ORFV D1701-V DNA genome.
  • the hatched boxes represent the insertion sites IL1, IL2, IL3 and vegf.
  • URL stands for the inverted terminal repeats of the genome ends.
  • the vector shows the AcGFP gene (line hatching), which is under the control of the artificial early promoter P1 (black arrow, above), and the mCherry gene (box hatching), which is under the control of the artificial early promoter P2 (black arrow, right) stands.
  • Behind both fluorescence genes are poxvirus-specific early transcription-stop motifs T5NT (black).
  • the genes are separated by a spacer (Sp). Multiple multiple cloning sites (MCS 1-6) allow the exchange of fluorescent marker genes by desired foreign genes.
  • the gene-containing flanked regions are downstream homologous to the ORFV genome region ORF1 17/1 18, upstream homologous to the ORFV genome region ORF1 14, and ensure site-directed integration into the IL 2 locus of the D1701-V genome via homologous recombination.
  • Fig. 3 shows an expression analysis of different fluorescent recombinants.
  • A, a Fluorescence micrograph of a 6-well plate with D1701-V-D2Cherry infected Vero cells. To select the recombinants, cherry-fluorescing plaques were picked and the virus grown from the plaques. After four plaque purifications, homogeneity of D1701 -V-D2Cherry was confirmed by PCR analysis.
  • (B) Fluorescence expression of the recombinant D1701-V-GFP-D2Cherry. Vero cells were infected with D1701 -V-GFP-D2Cherry (MOI 0.5). In the upper row, a fluorescence image can be seen 48 hours after infection (magnification: 20X). The bottom row shows the fluorescence expression 24 hours (magnification: 63X). Fluorescence microscopy allowed the representation of AcGFP (GFP), mCherry expression (mCherry), and both fluorescences in a cell (merged). In addition, the cells were recorded in the microscope transmitted light (transmitted light).
  • Uninfected Vero cells served as a negative control. M1 describes the range in which 99.39% of all uninfected cells (anterior first curve) are detected. In the M2 area, on the other hand, there are GFP-positive cells. The population of GFP-positive cells was comparable after infection with the GFP-expressing recombinants (38.2% -40.0%). It was evident that GFP intensity was lowest in D1701-V-D1 GFP-infected cells (solid line), and was strongest in D1701-V-D2GFP-infected cells (- - - -). (B) Vero cells were infected with mCherry-expressing recombinants (MOI ca.
  • Uninfected Vero cells served as a negative control. M1 describes the range in which 99.47% of all uninfected cells (front first curve) are detected. In area M2, however, there are cherry-positive cells. The population of mCherry positive cells was comparable after infection with the GFP-expressing recombinants (62.5% -63.3%). The mCherry intensity was significantly lower in D1701-V-Cherry-infected cells () than in D1701-V-D2Cherry (blue line) or in D1701-V2Cherry-infected cells (red line).
  • the ORFV genome consists of a linear double-stranded DNA and has a length of about 138 kb, a GC content of about 64% and has 130-132 genes.
  • the structure of the ORFV genome is similar to that of other poxviruses. It consists of a central region with essential genes that have a high degree of conservation within the Poxviridae.
  • the ORFV genome contains 88 genes that are conserved in all Chordopoxvirinae. In the terminal regions, viral genes are localized which are not essential for in vitro growth, but are relevant to the pathogenicity and tropism of the virus.
  • D1701 virus significantly enlarges the inverted terminal repeats (ITR). These changes not only led to the loss, but also to the duplication of some genes, as well as the vegf-e gene.
  • ITR inverted terminal repeats
  • the adaptation of the D1701-B in bovine BK-KL3A cells to the growth in Vero cells produced three further insertion sites IL 1, IL 2 and IL 3 in the virus genome of the now D1701-V designated virus. These are illustrated in FIG. 1.
  • Poxviruses have early, intermediate and late promoters
  • Promoters have some characteristic sequence properties which are exemplified by the example of VACV below.
  • the early promoter of the VACV consists of a 16 or 15 nucleotide critical region separated from a 7 nucleotide initiator region by a 1 1 nucleotide spacer region, the critical region is more adenine rich, whereas the spacer region is more thymic rich .
  • the Transcription initiation always occurs with rare exceptions on a purine. Nucleotide substitutions in the critical region can have a dramatic negative effect on promoter activity, even complete loss of activity is possible.
  • Substitution analyzes of the early VACV 7.5 kDa promoter provided an optimized critical region, and it was also possible to derive a consensus sequence for the "early" poxvirus promoter, which is shown in Table 1.
  • the "intermediate" promoters consist of an AT nucleotide sequence, which is about 14 nucleotides in length, followed by a 10-11 nucleotide spacer region followed by a short initiator region
  • the jate promoter assembly consists of an upstream, about 20 nucleotide AT-rich region bounded by a Spacer region is separated from the transcription start site of about 6 nucleotides, which contains the highly conserved sequence -1 TAAAT +4.
  • the inventors have searched for a new strategy for producing a recombinant polyvalent ORFV vector.
  • the transfer plasmid pDel2 was designed, which comprises the homologous regions of the IL 2 region ( Figure 2).
  • the cloning of foreign genes into the plasmid was made possible by the use of several MCS (multiple cloning sites).
  • the plasmid was designed to allow the simultaneous integration of multiple foreign genes, each under the control of artificial early ORFV promoters, and bounded by poxvirus-specific T5NT early transcriptional arrest motifs ( Figure 2).
  • Nucleotide sequences of the new artificial early ORFV promoters P1 and P2 were designed.
  • the mCherry fluorescent marker gene was cloned into the pDel2 transfer plasmid under the control of promoter P2. Subsequently, the plasmid was transfected into Vero cells infected with D1701VrV and new recombinant viruses were visually selected for identification of red-shining cells by fluorescence microscopy and the homogenous recombinant D1701-V-D2-Cherry obtained via several pseudoparations was grown (FIG. 3A, a).
  • the simultaneous early expression of two fluorescent genes in different insertion loci was successful detected (Fig. 3B). Furthermore, it should be investigated whether a second foreign gene can be stably integrated into the IL 2 locus at the same time.
  • the AcGFP gene was cloned into the pDel2 transfer plasmid under the control of the P1 promotor. The selection and purification of the homologous recombinants D1701 -V-D1-GFP-D2-Cherry was carried out analogously to the previously described D1701 -V-P2-Cherry selection.
  • the strength of the promoters P1 and P2 was compared with each other and with the promoter P vegf in expression analyzes . It showed that the promoter P2 induced the strongest, the promoter P1 the weakest gene expression (Fig. 4A + 4C). This was surprising since P1 corresponds to 100% of the vaccinia virus consensus sequence, but not P2.
  • Orf virus vector D1701-V is very well suited for the production of polyvalent recombinants.
  • Several foreign genes could be stably integrated into the viral genome, for example via the newly found insertion locus IL 1, 2 and 3, or else the known insertion locus VEGF.
  • the strength of foreign gene expression is evident both from the promoter and from the insertion kus dependent. The strongest gene expression was achieved after integration of a P2-driven foreign gene in the VEGF locus.
  • the inventors have produced further different vectors, which differ from one another by the nature and constellation of the different marker foreign genes, insertion sites and promoters (Table 2).
  • Tab. 2 Tabular overview of the newly prepared fluorescent ORFV vectors.
  • the table gives an overview of the fluorescent recombinant ORFV vectors produced during the work leading to the invention.
  • the insertion site (locus) and the promoters used for the control of foreign gene expression (P ve g f , P 1, P 2) are apparent for the respective recombinants in the table.
  • the invention opens up a variety of options for the development of new recombinant ORFV-based vaccines.
  • recombinants can be produced which simultaneously express several antigens. This could be a significant advantage in the manufacture of, for example, a universal vaccine, combination vaccines, or therapeutic tumor vaccines that target multiple tumor antigens.
  • the immune response could be specifically influenced by a simultaneous insertion of antigen and cytokines.

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Abstract

La présente invention concerne un vecteur de virus Orf recombiné, une cellule contenant le vecteur de virus Orf recombiné, une composition contenant le vecteur de virus Orf recombiné selon l'invention et/ou la cellule selon l'invention, l'utilisation du vecteur de virus Orf recombiné selon l'invention pour la préparation d'un gène étranger et une molécule d'acide nucléique codant pour un promoteur du vecteur de virus Orf.
PCT/EP2016/066926 2015-07-20 2016-07-15 Vecteur de virus orf recombiné Ceased WO2017013023A1 (fr)

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EP25156960.4A EP4545094A3 (fr) 2015-07-20 2016-07-15 Vecteur de virus orf recombiné
KR1020187004903A KR102259277B1 (ko) 2015-07-20 2016-07-15 재조합 ｏｒｆ 바이러스 벡터
CA2993263A CA2993263A1 (fr) 2015-07-20 2016-07-15 Vecteur de virus orf recombine
CN201680053548.XA CN108026542B (zh) 2015-07-20 2016-07-15 重组Orf病毒载体
BR112018001121-5A BR112018001121B1 (pt) 2015-07-20 2016-07-15 Vetor recombinante do vírus orf (orfv), composição, uso de um vetor recombinante de orfv, e, molécula de ácido nucleico
DK16741595.9T DK3325631T3 (da) 2015-07-20 2016-07-15 Rekombinant orf-virusvektor
KR1020217015985A KR102433709B1 (ko) 2015-07-20 2016-07-15 재조합 ｏｒｆ 바이러스 벡터
EP16741595.9A EP3325631B1 (fr) 2015-07-20 2016-07-15 Vecteur de virus orf récombiné
NZ73928616A NZ739286A (en) 2015-07-20 2016-07-15 Recombinant orf virus vector
IL257025A IL257025B2 (en) 2015-07-20 2016-07-15 Recombinant orf virus vector
EA201890351A EA201890351A1 (ru) 2015-07-20 2016-07-15 Рекомбинантный orf-вирусный вектор
AU2016294855A AU2016294855B2 (en) 2015-07-20 2016-07-15 Recombinant Orf virus vector
MX2018000845A MX2018000845A (es) 2015-07-20 2016-07-15 Vector vírico orf recombinante.
JP2018522854A JP7092663B2 (ja) 2015-07-20 2016-07-15 組換えオルフウイルスベクター
CN202211462316.3A CN116445547A (zh) 2015-07-20 2016-07-15 重组Orf病毒载体
US15/875,389 US11286500B2 (en) 2015-07-20 2018-01-19 Recombinant Orf virus vector
PH12018500155A PH12018500155A1 (en) 2015-07-20 2018-01-19 Recombinant orf virus vector
ZA2018/01091A ZA201801091B (en) 2015-07-20 2018-02-16 Recombinant orf virus vector
AU2020264302A AU2020264302B2 (en) 2015-07-20 2020-11-04 Recombinant Orf virus vector
US17/655,316 US20220204992A1 (en) 2015-07-20 2022-03-17 Recombinant orf virus vector

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WO2019170820A1 (fr) * 2018-03-07 2019-09-12 Transgene Vecteurs de parapoxvirus
CN112512560A (zh) * 2018-03-07 2021-03-16 特兰斯吉恩股份有限公司 副痘病毒属载体
JP2021516957A (ja) * 2018-03-07 2021-07-15 トランジェーヌＴｒａｎｓｇｅｎｅ パラポックスウイルスベクター
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AU2019229653B2 (en) * 2018-03-07 2025-09-11 Transgene Parapoxvirus vectors
EP3957322A1 (fr) 2020-08-19 2022-02-23 Eberhard Karls Universität Tübingen Medizinische Fakultät Vecteur de poxviridae recombinant exprimant des molécules co-stimulatrices
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